Lysosomes are the primary site for degradation of normal cellular constituents. Over 30 inheritable "storage diseases" are caused by specific defects in lysosomal hydrolase activities. Defective lysosomal function is also characteristic of aging and various nutritional disorders. Lysosomal injury during acquired diseases results in extracellular release of activated hydrolase which often produces necrosis and cell death. The mannose 6-phosphate receptor is responsible for localization of many hydrolases in lysosomes. It binds the hydrolases immediately after their synthesis and facilitates their packaging into lysosomes. The receptor also functions on the cell surface to facilitate removal of acid hydrolases from extracellular sites. The long range goal is to determine the molecular basis of mannose 6-phosphate receptor function. Recombinant DNA techniques will be used to introduce structural changes in the receptor, biologic methods will be used to examine their effects on specific aspects of receptor function. The immediate objectives of this proposal, namely to clone a cDNA encoding the mannose 6-phosphate receptor and determine the structure of the receptor, provide the basis for achieving this goal. These studies will contribute to our understanding of lysosome biogenesis, intracellular membrane trafficking and protein sorting.